Pathogenesis of Obesity and Type 2 Diabetes
Type 2 diabetes is characterized by insulin resistance following progressive decline in β-cell function in the pancreatic islets.
The treatment of type 2 diabetes is mainly limited to metformin monotherapy as the initial strategy to improve insulin sensitivity. When the patient cannot control glycaemia by lifestyle and metformin, a therapeutic strategy to increase β-cell function and insulin sensitivity will be required, as an alternative to chronic exogenous insulin injections.
Group Leader, Esteban Gurzov, Ph.D.
Research Interests
The role of JAK-STAT signalling in obesity.
Type 2 diabetes is generally related to obesity, a risk factor for the disease. The transition from obesity to diabetes is complex and involves the interplay between multiple signalling pathways and body systems that remain to be clarified. The JAK-STAT proteins are critical cell signalling molecules. The regulation of the STAT family of transcription factors in metabolic tissues (brain, pancreas, muscle, liver and adipocytes) is affected during obesity and type 2 diabetes. In this project, we will take advantage of human stem cells and CRISPR gene editing to directly elucidate mechanisms modulated by aberrant signalling in differentiated metabolic cells. The differentiation method has been successfully implemented in our lab with the generation of insulin-positive β-cells and albumin-positive-hepatocytes (collaboration with David Hay). Our knowledge accumulated in recent years enable us to study the mechanisms by which different subcomponents of the JAK-STAT signalling influence metabolic physiology, i.e. acting as regulators of liver homeostasis, food intake, or β-cell dysfunction. (Figure adapted from Gurzov EN, et al. FEBS 2016)
Selected Publications
Schaschkow A, Pang L, Vandenbempt V, Elvira B, Litwak SA, Vekeriotaite B, Maillard E, Vermeersch M, Paula FM, Pinget M, Perez-Morga D, Gough DJ, Gurzov EN. STAT3 regulates mitochondrial gene expression in pancreatic β-cells and its deficiency induces glucose intolerance in obesity. Diabetes 70(9):2026-2041, 2021
Gurzov EN, Ke PC, Ahlgren U, Garcia Ribeiro RS, Gotthardt M. Novel Strategies to Protect and Visualize Pancreatic β Cells in Diabetes. Trends Endocrinol Metab 31(12):905-917, 2020
Litwak SA, Pang L, Galic S, Igoillo-Esteve M, Stanley WJ, Turatsinze J-V, Loh K, Thomas HE, Sharma A, Trepo E, Moreno C, Gough DJ, Eizirik DL, de Haan JB, Gurzov EN JNK activation of BIM promotes hepatic oxidative stress, steatosis and insulin resistance in obesity. Diabetes 66:2973 -2986, 2017
Gurzov EN, Stanley WJ, Pappas EG, Thomas HE, Gough DJ. The JAK/STAT Pathway in Obesity and Diabetes. FEBS J 283:3002-3015, 2016
Litwak SA, Stanley WJ, Pappas EG, Wali JA, Selck C, Strasser A, Thomas HE, Gurzov EN. p53-upregulated modulator of apoptosis (PUMA)-deficiency affects leptin levels but does not improve glucose homeostasis in obesity. Sci Rep 6:23802, 2016
Gurzov EN, Wang B, Pilkington EH, Chen P, Kakinen A, Stanley WJ, Litwak SA, Davis TP, Ding F, Ke PC. Inhibition of hIAPP Amyloid Aggregation and Pancreatic beta cell Toxicity by OH-terminated PAMAM Dendrimer. Small 12:1615-1626, 2016
Gurzov EN, Stanley WJ, Brodnicki TC, Thomas HE. Protein tyrosine phosphatases: molecular switches in metabolism and diabetes. Trends Endocrinol Metab 26:30-39, 2015
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